Estrogenic compounds and animal growth promoters



United States Patent 3,373,034 ESTROGENIC COMPOUNDS AND ANIMAL GROWTH PRQMGTERS Edward B. Hodge, Phil H. Hidy, and Herbert L. Wehrrneister, Terre Haute, Ind., assignors to Commercial Solvents Corporation, a corporation of Maryland No Drawing. Continuation-in-part of application Ser. No. 561,372, June 29, 1966. This application Mar. 3, 1967, Ser. No. 620,271.

Claims. (Cl. 992) ABSTRACT OF THE DISCLOSURE Where R is selected from the group consisting of hydrogen, benzyl, and lower alkyl, A is a radical selected from the group consisting of -CH=CH- and -CH CH and R is selected from the group consisting of hydrogen and halogen, with the proviso that at least one R is halogen; and animal feeds containing growth promoting amounts thereof.

where A is CH -CH or CH=CH; R is hydrogen, substituted or unsubstituted alkyl, e.g., lower alkyl such as methyl, ethyl, hexyl, etc. or aralkyl, e.g. benzyl; and R is hydrogen or halogen, such as bromine, chlorine, fluorine and iodine, with the proviso that at least one R is halogen.

The compounds of the present invention can be produced from the compound:

H-O f E C-O-CH-(CHils C=O H-O OH=CH-( 2)a hereinafter referred to as the fermentation estrogenic substance (F.E.S.). It is desirable to protect the hydroxyl groups on the benzene ring of F.E.S. against undesirable side reactions before halogenation which can be accomplished by converting the hydroxyl groups to others, e.g.,

methylethers, as taught in US. Patent 3,239,342 and subsequently removing the masking group to regenerate the hydroxyl group. The hydroxyl group can be regenerated from, for example, a methyl ether by hydrolysis or by refluxing in acetic acid solution with hydrobromic acid. Aluminum chloride is another effective dealkylat- 3,373,034 Patented Mar. 12, 1968 ing agent. A benzyl radical is a preferred masking group. Benzyl ethers of F.E.S. are described in copending application Ser. No. 532,113 filed Mar. 7, 1966, now abancloned, and application Ser. No. 620,259, filed Mar. 3, 1967. US. Patent 3,239,354 describes dihydro F.E.S. compounds where A is CH -CH Tetrahydro F.E.S. wherein the keto-group is reduced is described in U.S. Patent 3,239,354.

The compounds can be administered to animals by any suitable method including oral and parenteral administrations. For example, the compound can be blended with ordinary fed containing nutritional values in an amount suflicient to produce the desired rate of growth and can thus be fed directly to the animals, or the compound can be suspended in a suitable injection suspension medium such as peanut oil and injected parenterally. The amount of compound fed to an animal, of course, varies depending upon the animal, desired rate of growth and the like.

When the new compounds are to be administered in feeds, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities ofcarbohydrates, proteins, vitamins and minerals, together with the compound of the present invention. Some of these usual dietary elements are grains, such as ground grain and grain by-products; animal protein substances, such as those found in fish meal and meat scraps, vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle includes alfalfa hay and ground corn cobs together with supplementary vitaminaceous substances if desired.

The following examples serve to illustrate the invention.

EXAMPLE I F.E.S. 2,4-dimethylether in diethyl ether is added to Dihydro F.E.S. 2,4-diethylether is substituted for F.E.S. 2,4-dimethylether in Example I to produce The dichloro derivative produced according to Example I is added to an acetone solution containing a molar excess of potassium iodide to produce:

o o o ,u 3 EXAMPLE IV Tetrahydro F.E.S. 2,4-diethyl ether in benzene solution is reacted with phosphorous tribromide in pyridine. The product is:

I1 CHzC a 2) 3 EXAMPLE V The compound produced according to Example I is demethylated by heating at 120 C. in benzene solution with two equivalents of aluminum chloride to produce EXAMPLE VI To tetrahydro RES. 2,4-dimethylether in benzene is added pyridine and then thionyl chloride. The resulting mixture is warmed on a steam bath for several hours and then stirred with ice. The product is:

EXAMPLE VII The monochloro derivative produced according to Example VI. is reacted with KI according to Example III to produce the corresponding monoido derivative.

EXAMPLE VIII The monochloro derivative of Example VI is demethylated according to the process of Example V.

EXAMPLE IX Six head of cattle are fed a daily ration of alfalfa hay and ground corn cobs containing 5 to ounces of the compound of Example I per 100 pounds feed and their rate of growth is improved.

EXAMPLE X Six head of cattle are fed a daily ration of alfalfa hay and ground corn cobs containing 5 to 20 ounces of the compound of Example VI per 100 pounds feed and their rate of growth is improved.

EXAMPLE XI Six head of cattle are fed a daily ration of alfalfa hay and ground corn cobs containing 5 to 20 ounces of the compound of Example III per 100 pounds feed and their rate of growth is improved.

EXAMPLE XII HaCO 4 EXAMPLE XIII For young beef cattle, i.e., calves to yearlings running to two-year-olds, each animal is given 5 to 20 milligrams per day of the compound produced in Example I intimately admixed in about 18 to 22 pounds per head per day of a complete pelleted ration for about 180' days. The complete pelleted ration includes in addition to the compounds of Example I the following:

Barley percent 4043 Molasses dried beet pulp do 34.537.5 Alfalfa pellets ..do 8.0 Tallow do 2.5 Calcium carbonate do .30 Urea do .30 Phosphorus source do .40 Salt -do .50 Molasses do 10.00 Trace mineral do 0.5 Vitamin A I.U./ton 2-4MM Note-Milo or corn, for example, can be substituted for the barley.

The compound of Example I is admixed with the above ingredients in a stationary blender or a feed mix truck in the following amounts in grams per ton to provide an appropriate complete pelleted feed with dosage levels ranging from 5 to milligrams per head per day.

These gram amounts are premixed with, for example, 10 pounds of soybean hulls prior to admixture with the other ingredients.

EXAMPLE XIV For young swine, i.e., six-week-old pigs to about 10 0- pound pigs, each animal is given 5 to 20 milligrams per day of the compound of Example II intimately admixed in about 1 /2 to 5 /2 pounds per head per day of a grower ration until it reaches a weight of about pounds. When the swine weigh between 90 and pounds the feed is changed to one whereby each animal is given 20 to 50 milligrams per day of the compound of Example II intimately admixed in about 5 /2 to 10 pounds per head per day of a finisher ration until it reaches market weight of about 220 pounds. The grower and finisher ration include in addition to the compound of Example II the following:

ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate feed with dosage levels ranging from 6 to 96 milligrams per head per day.

Mg./pound: Mg./head/day 6 EXAMPLE XV For 4- to IO-month-old lambs weighing 50 to 70 pounds, each animal is given 1 to 15 milligrams per day of the compound of Example V, intimately admixed in about 3 to 6 pounds per head per day of a complete ration for 30 to 90 days. The complete ration includes in addition to the compound of Example V the following:

The compound of Example V is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate complete feed with dosage levels ranging froml to 15 milligrams per head per day.

Mg./pound: Mg./head/day .5 2 1.0 4 1.5 6 2.0 8 2.5 10 3.75

EXAMPLE XVI For broilers, i.e., day-old to four-week-old chicks, a grower feed is prepared for feeding to the chicks for the first four weeks and a finisher feed is prepared for feeding the four-week-old chicks for the last five weeks until they reach market weight of two and a half to three pounds dressed. For each pound of weight gain, the chicks eat about 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feed during the first four weeks and about five pounds of feed during the next five weeks. During the course of this feeding schedule, each bird should receive a total of about 12 to .36 milligrams of the compound of Example VI in the grower and finisher feed each of which includes in addition to the compound of Example VI the following:

Grower Finisher (lbs.) (lbs) Ground Yellow Corn l, 000 1, 200 Soybean Meal (44% Protein).-- 700 500 Fish Meal (60% Protein) 100 80 Alfalfa Meal- 50 50 Meat and Bone Scraps 0 Animal Fat 80 80 Dicalcium Phosphate Iodized Salt 10 10 Limestone l l 15 Premix Vitamins Trace Minerals and Antibioties 1O 10 What is claimed is:

where R is selected from the group consisting of hydrogen, benzyl, and lower alkyl, A is a radical selected from the group consisting of CH=CH and CH -CH and R is selected from the group consisting of hydrogen and halogen, with the proviso that at least one R is halogen.

2. The compound of claim 1 where A is -CH=CH-.

3. The compound of claim 1 where R is hydrogen and A is CH2CH2 4. The compound of claim 1 and A is -CH=CH.

5. The compound of claim 4 wherein both R s are halogen.

6. The compound of claim 1 where R is lower alkyl and A is CH CH 7. The compound of claim 6 wherein b-oth R s are halogen.

8. The compound of claim 6 wherein one R is hydrogen.

9. The compound of claim 8 wherein the other R is chlorine.

10. An animal feed composition comprising a nutrient ration and a growth promoting amount of the compound of claim 1.

R is hydrogen and where R is lower alkyl No references cited. A. LOUIS MONACELL, Primary Examiner.

H. H. KLARE III, Assistant Examiner. 

